Project Summary/Abstract Antimicrobial peptides (AMPs) are a broad classification assigned to many gene products that have the ability to kill or inhibit the growth of microbes. Cathelicidins are a major family of AMPs that are expressed in vertebrates to provide defense against infection, and inactivated by pathogens as a mechanism to enhance virulence. Although the cathelicidin gene is evolutionarily conserved within vertebrates, the sequence of exon 4 of the cathelicidin gene has diverged significantly between species. This exon encodes the carboxy-terminus of the precursor protein that is post-translationally processed into the final mature AMP. The structure of this mature peptide is critical for function within the specific defense context. For example, the human cathelicidin gene CAMP if expressed as the mature peptide LL37 has potent pro-inflammatory activity in addition to its capacity to kill microbes. This provides enhanced host defense during infection when such expression is appropriate, but promotes several human skin diseases where inappropriate expression occurs. Because cathelicidin appears to drive human inflammatory diseases such as rosacea and psoriasis, it is important to understand the mechanism of action of this unique AMP. The basis of this renewal proposal are exciting new preliminary data that have provided a breakthrough in understanding how LL37 mediates inflammation. Findings suggest that LL37 mediates receptor-dependent recognition of nucleic acids. We have termed this process ?innate immune vetting? since we hypothesize that LL37 dictates if nucleic acids will induce an inflammatory response. The overall goal of this renewal application is to better understand the mechanism by which LL37 triggers inflammation and explore potential strategies that will modify this event and treat disease.